The interplay of intramolecular interactions that affect structural heterogeneity has eluded experimental investigation in the context of IDPs. Here we use polymer physics models combined with SAXS and trFRET to characterize the structural heterogeneity of a model IDP. Overall, the result by both SAXS and trFRET shows that the NFLt consists of intramolecular structural heterogeneity - different domains within the IDP occupy space differently, although all display disorder properties. While NFLt can be defined as a strong polyampholyte (FCR = 0.45 and NCPR = 0.24)[1]}, introspection of sub-segments shows sequence heterogeneity that ranges from polymer description as weak polyampholyte to strong polyelectrolyte. Consistently, we find that Flory's exponent is scaling from chain in theta solvent with \(\nu =0.5\)  to chain in good solvent with \(\nu =0.6\)  and further stretching up to \(\nu =0.7\)  in the IDP context. While the segments' expansion correlates well with the net charge at low ionic strength [2]} (Fig. REF ), and the order parameter that combines the sequence hydropathy and charge decoration [3]} (Fig. REF ), the additional expansion in the context of the protein is beyond current modeling. Nonetheless, such scalings promote the ability to predict the ensemble structure of IDPs segments from their sequence. Interestingly, the scaling correlation with NCPR is tuned down with increasing salinity pointing towards dominant electrostatic interaction.
